Cytokine Control of Nitric Oxide Production: Therapeutic Possibilities

From studies aiming to determine the source of potentially carcinogenic nitrogen compounds within mammals, it was found that cells of the immune system were capable of producing reactive nitrogen intermediates (Green et al. 1981; Stuehr and Marietta 1985). Following the discovery that nitric oxide (NO) was the chemical identity of endothelium-dependent relaxing factor, it was quickly realised that NO was the origin of reactive nitrogen intermediates from activated immune cells. Since that time, it has become clear that a large number of different cells can be stimulated to produce NO, ranging from vascular smooth muscle cells to astrocytes (Nathan and Xie 1994). The stimuli required to produce this NO production are generally pro-inflammatory cytokines and bacterial components such as lipopolysaccharide (LPS). Molecular cloning of the genes responsible for NO production has identified the gene product responsible for cytokine activated NO production, which has been termed inducible NO synthase (iNOS) or type II NOS (Forstermann et al. 1994). This has considerable homology to the constitutive NOS isoforms found in brain and endothelium, as would be expected of enzymes catalysing the same reaction. However, there are important differences. Most notably, iNOS is not ordinarily subject to control by intracellular calcium ion concentrations, so that once induced iNOS produces large and sustained amounts of NO (Vodovotz et al. 1994).